Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome.

BACKGROUND: The dichotomy between ovulation rates and pregnancy rates for women with polycystic ovary syndrome (PCOS) treated with clomiphene citrate (CC) prompted the present study to determine the effect of CC on endometrial maturity. METHODS: Retrospective case-control study of anovulatory women with PCOS (n = 119) on their third ovulatory cycle of CC and controls, 238 healthy regularly ovulating women whose partners had abnormal sperm, all of whom had an endometrial biopsy in the late luteal phase. RESULTS: Endometrial histology classified according to the classical Noyes criteria revealed out-of-phase endometrium in 19/119 (16%) of the CC group compared with 7/238 (3%) in controls (p < 0.0001). Duration of the luteal phase was not influenced by histological age of the endometrium. Endometrial biopsy performed during 138 conception cycles extracted from the database did not increase the miscarriage rate significantly (23.9%). CONCLUSIONS: CC treatment significantly increases the prevalence of out-of-phase endometrium and this could explain, in part, the large difference between ovulation and pregnancy rates. There was no correlation between the results of the endometrial biopsy and the duration of the luteal phase. Performing an endometrial biopsy during a conception cycle does not seem to have a significant negative effect on the outcome of pregnancy.     

Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome

Background.?The dichotomy between ovulation rates and pregnancy rates for women with polycystic ovary syndrome (PCOS) treated with clomiphene citrate (CC) prompted the present study to determine the effect of CC on endometrial maturity.

Methods.?Retrospective case–control study of anovulatory women with PCOS (n = 119) on their third ovulatory cycle of CC and controls, 238 healthy regularly ovulating women whose partners had abnormal sperm, all of whom had an endometrial biopsy in the late luteal phase.

Results.?Endometrial histology classified according to the classical Noyes criteria revealed out-of-phase endometrium in 19/119 (16%) of the CC group compared with 7/238 (3%) in controls (p < 0.0001). Duration of the luteal phase was not influenced by histological age of the endometrium. Endometrial biopsy performed during 138 conception cycles extracted from the database did not increase the miscarriage rate significantly (23.9%).

Conclusions.?CC treatment significantly increases the prevalence of out-of-phase endometrium and this could explain, in part, the large difference between ovulation and pregnancy rates. There was no correlation between the results of the endometrial biopsy and the duration of the luteal phase. Performing an endometrial biopsy during a conception cycle does not seem to have a significant negative effect on the outcome of pregnancy.     

自然及促排卵周期子宫内膜整合素α4β1的表达

目的 了解氯米芬（CC）、绝经期促性腺激素（hMG）对黄体中期子宫内膜整合素α4β1表达的影响。方法 应用单克隆抗体,采用免疫组织化学技术检测48例正常妇女自然周期以及48例正常妇女、30例多囊卵巢综合征患者应用CC／绒毛膜促性腺激素（hCG）及CC／hMG/hCG方案促卵治疗后黄体中期子宫内膜整合素α4β1的表达。结果 子宫内膜整合素α4β1在正常妇女自然周期着床窗口期呈现强阳性表达,而CC、hMG抑制整合率α4β1的表达,两者比较,差异有极显著性（P＜0．01）;妊娠者较妊娠者整合素α4β1表达强度高。结论 促排卵周期黄体中期整合素α4β1表达下降或缺失,子宫内膜容受性下降,妊娠率降低。     

Effects of clomiphene citrate on cytosolic estradiol and progesterone receptor concentrations in secretory endometrium

Cytosolic estradiol and progesterone receptor concentrations were measured in luteal phase endometrial biopsy samples obtained from 12 anovulatory or oligoovulatory women on clomiphene citrate therapy and from 40 normal control subjects. Clomiphene citrate treatment (250 to 750 mg per cycle) decreased both endometrial estradiol and progesterone receptor concentrations. Estradiol receptor levels were nondetectable in seven tissue samples and progesterone receptor levels in four samples from the 12 subjects given clomiphene citrate compared to nondetectable estradiol receptor concentrations in one tissue sample and progesterone receptor concentrations in two samples from the 40 normal control subjects. In histologically dated endometrium, mean estradiol receptor concentrations on days 20 to 23 and progesterone receptor levels on days to 24 to 27 were lower than the values observed in the comparable dated endometrium of normal ovulatory women. Steroid receptor concentrations correlated negatively with the duration of clomiphene citrate therapy, which implies a time-dependent suppressive effect of clomiphene citrate on measurable cytosolic estradiol and progesterone receptor concentrations during the luteal phase of the cycle.     

Surgical treatment in polycystic ovary syndrome

PURPOSE OF REVIEW: The purpose of this review is to provide a critical summary of current knowledge on the role and effectiveness of ovarian surgery in the treatment of polycystic ovary syndrome. RECENT FINDINGS: Clomiphene citrate is used as a first-line treatment for ovulation induction in infertile anovulatory patients with polycystic ovary syndrome. In clomiphene citrate-resistant women, other treatment modalities such as laparoscopic electrocautery or ovulation induction with gonadotropins have been proposed as alternative therapies. Although gonadotropin treatment and laparoscopic ovarian drilling have demonstrated similar reproductive outcomes, laparoscopic ovarian drilling has some advantages over gonadotropin treatment such as lower cost per pregnancy, improvement in menstrual regularity, and better long-term reproductive performance. On the other hand, knowledge about the pathogenesis of polycystic ovary syndrome has been growing and insulin-sensitizing drugs have gained popularity as a new treatment option. SUMMARY: According to current data, metformin has gained popularity as first-line management in clomiphene citrate-resistant women with polycystic ovary syndrome. If ovulation does not occur within several months after treatment with metformin, after the evaluation of all pros and cons related to each treatment, laparoscopic ovarian drilling or gonadotropins may be considered as an effective option according to patient choice.     

Ovulation induction in anovulatory women

Ovulation induction therapy is administered to stimulate follicular growth and induce ovulation in anovulatory infertile women. In anovulatory women with polycystic ovary syndrome, the treatment of choice is clomiphene citrate, whereas in clomiphene nonresponders, gonadotrophins are given as secondary therapy. Currently, insulin-sensitizing agents are used in the treatment of polycystic ovary syndrome to restore menstrual cyclicity. In selected patients, laparoscopic drilling has also been suggested. In anovulatory patients affected with hypogonadotropic hypogonadism, treatment is based on gonadotrophin replacement therapy or pulsatile gonadotrophin-releasing hormone infusion. In ovulation induction therapy the clinician's attention should be directed at restoring normal ovary function. When pharmacotherapy is required, monofollicular growth should be induced to reduce the risk of multiple pregnancy.     

Laparoscopic electrosurgical furrowing technique for the treatment of polycystic ovaries

A retrospective analysis of reproductive outcomes was conducted in 30 anovulatory women treated with a new laparoscopic electrosurgical furrowing technique. All patients had polycystic ovary syndrome refractory to ovulation induction with clomiphene citrate and gonadotropin therapy. Bilateral ovarian furrowing was success-fully accomplished in all 30 patients without technical difficulty or surgical complications. Average furrowing time was 5 minutes per ovary and all patients were discharged by 12 hours postoperatively. Regular ovulatory function resumed in 25 women (83.3%); the 5 refractory patients were administered clomiphene citrate. Spontaneous conception occurred in 21 ovulatory patients (70.0%) and clomiphene-assisted conception occurred in 3 of the 5 refractory women, for an overall pregnancy rate of 80% (24/30). Twenty-three pregnancies resulted in viable term deliveries; one (4.2%) ended in a first-trimester abortion. These results suggest that the laparoscopic electrosurgical furrowing technique for the treatment of anovulatory infertility in women with polycystic ovary syndrome refractory to clomiphene citrate and gonadotropin therapy is effective, safe, and easily performed. Further evaluation is warranted to confirm the appropriateness of this procedure.     

Comparison of metformin and clomiphene citrate therapy for induction of ovulation in the polycystic ovary syndrome

Objective  

To compare the efficacy of metformin and clomiphene citrate (CC) therapies for ovulation induction in anovulatory infertile women with polycystic ovary syndrome (PCOS).     

A prospective, randomised, cross-over study comparing the effects of clomiphene citrate and cyclofenil on endometrial morphology in the luteal phase of normal, fertile women.

OBJECTIVE: To examine the effect of two anti-oestrogens, clomiphene citrate and cyclofenil, on endometrial morphology in the luteal phase. DESIGN: A prospective, randomised, cross-over study. SETTING: Jessop Hospital for Women, Sheffield, UK. SUBJECTS: 10 women who were previously fertile and regularly cycling. INTERVENTION: The administration of clomiphene citrate or cyclofenil in the treatment cycles. A LH timed endometrial biopsy was taken on day LH + 6. MAIN OUTCOME MEASURES: Histological dating and morphometric analysis of the endometrial sample. RESULTS: Only one out of 10 subjects had abnormal endometrium. There was no difference in the results between cycles treated with clomiphene citrate and cyclofenil. CONCLUSIONS: Clomiphene citrate or cyclofenil does not have a major adverse effect on endometrial morphology in the luteal phase of normal fertile subjects. The possible adverse effects of anti-oestrogens on endometrium may have been previously overestimated.     

Aetiology,investigation and management of ovulatory problems

Anovulatory patients typically present with infertility. They and their partners should both be seen and examined and an ovulation plan should be developed with their doctor. A diagnosis for the symptoms and signs of chronic anovulation must be made of which polycystic ovary syndrome, hypogonadotrophic hypogonadism and hyperprolactinemia are most frequent. Pre-pregnancy counselling before ovulation induction includes not only advice re weight optimisation and cessation of smoking but also advice regarding multiple pregnancy, birth defects, ovarian hyperstimulation syndrome and multiple pregnancy reduction. Empirical therapies, such as clomiphene citrate administration to infertile but ovulatory women, should not be prescribed. Clomiphene or bromocriptine treated patients who remain anovulatory and are requiring gonadotrophin releasing hormone GnRH or gonadotrophin therapies should be referred to units experienced in such care.     

多囊卵巢综合征手术治疗的利与弊

多囊卵巢综合征是育龄期妇女最常见的一种内分泌紊乱性疾病,排卵障碍是该类患者不育的主要原因,常用解决方法为促排卵治疗。促排卵药物,例如氯米芬临床效果好,普遍采用。但是,部分患者耐药。手术治疗,特别是腹腔镜下卵巢打孔术是目前用于氯米芬耐药的多囊卵巢综合征患者促排卵治疗的二线治疗方案,本文就卵巢手术的主要方式、腹腔镜下卵巢打孔术的适应人群、术后效果及手术并发症进行简单概括。     

Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of metformin therapy on hyperandrogenism, insulin resistance, cervical scores, ovulation, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Infertility clinic of a tertiary referral center. PATIENT(S): Fifty-six women with clomiphene citrate-resistant PCOS. INTERVENTION(S): Two cycles of oral metformin therapy (850 mg, twice daily) in group I and placebo therapy (twice daily) in group II. Clomiphene citrate (100 mg/day) on cycle days 3-7 of the second cycle in both groups. MAIN OUTCOME MEASURE(S): Insulin, T, DHEAS, FSH, LH, body mass index (BMI), waist-to-hip ratio, endometrial thickness, cervical score, ovulation, and pregnancy rates in clomiphene-induced cycles after metformin therapy. Result(s): Metformin therapy resulted in a significant decrease in total T, LH level, LH/FSH ratio, insulin resistance, and mean BMI. No difference in waist-to-hip ratio, DHEAS level, and fasting insulin level was observed. Clomiphene citrate induction resulted in higher ovulation rates and thicker endometrium in the metformin group than in the placebo group. There was higher cumulative pregnancy rate in the metformin group; however, there was no significant difference in the pregnancy rate between the two groups. CONCLUSION(S): Metformin therapy not only decreases hyperandrogenism and insulin resistance but also improves ovulation rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with PCOS.     

Histology of midluteal corpus luteum and endometrium from clomiphene citrate-induced cycles.

OBJECTIVE: To determine the histologic development of midluteal corpus luteum (CL) and endometrium in normal fertile women after induction of ovulation with clomiphene citrate (CC). DESIGN, PATIENTS, INTERVENTIONS: Twelve normally cycling women planning to undergo an elective tubal ligation were treated with 50 to 150 mg of CC daily on days 5 through 9 of the cycle. Luteectomy and endometrial biopsy were performed simultaneously 7 days after the urinary luteinizing hormone surge. RESULTS: Because polyovulation occurred in 10 of the 12 women, 22 CL and 12 endometrial biopsies were studied. Ten women had luteal and endometrial histology that were within 2 days of the ovulation to biopsy interval. The 2 remaining women had endometrial histology that lagged 3 days behind the chronological postovulatory date. In these women, out-of-phase endometrium occurred despite polyovulatory cycles in which two and three histologically normal CL lutea were present and associated with elevated progesterone concentrations. CONCLUSIONS: In CC-induced ovulatory cycles: (1) midluteal CL histology is normal and (2) apparently out-of-phase preimplantation endometrium occurs in midluteal phase.     

Induction of ovulation in infertile women with hyperandrogenism and insulin resistance

The polycystic ovary syndrome is a common cause of anovulatory infertility. Women with severe insulin resistance are a unique subset of polycystic ovary syndrome. The syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) is one presentation of the insulin-resistant subset of polycystic ovary syndrome. Insulin resistance and hyperandrogenism are caused by genetic and environmental factors. In women with anovulatory infertility caused by hyperandrogenism and insulin resistance, clomiphene citrate treatment often fails to result in pregnancy. For these women, weight loss and insulin sensitizers can be effective methods of inducing ovulation and pregnancy and may reduce the number of clomiphene-resistant women with polycystic ovary syndrome who are treated with gonadotropins, ovarian surgery, or in vitro fertilization-embryo transfer.     

N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial

OBJECTIVE: To compare clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for inducing ovulation in patients with polycystic ovary syndrome. DESIGN: Prospective cross-over trial. SETTING: University teaching hospital and a private practice setting. PATIENTS: Five hundred and seventy-three patients were treated with clomiphene citrate for one menstrual cycle among which 470 patients were treated with clomiphene citrate plus N-acetyl cysteine for another cycle. All women suffered from polycystic ovary syndrome. INTERVENTIONS: Patients had clomiphene citrate 50-mg tablets twice daily alone or with N-acetyl cysteine 1,200 mg/day orally for 5 days starting on day 3 of the menstrual cycle. OUTCOME MEASURES: Primary outcomes were number of mature follicles, serum E2, serum progesterone, and endometrial thickness. Secondary outcome was the occurrence of pregnancy. RESULTS: Ovulation rate improved significantly after the addition of N-acetyl cysteine (17.9% versus 52.1%). Although the number of mature follicles was more in the N-acetyl cysteine group (2.1+/-0.88 versus 3.2+/-0.93), the difference was not statistically significant. The mean E2 levels (pg/ml) at the time of human chorionic gonadotropine injection, serum progesterone levels (ng/ml) on days 21-23 of the cycle, and the endometrial thickness were significantly improved in the N-acetyl cysteine group. The overall pregnancy rate was 11.5% in the N-acetyl cysteine group. Insulin resistance occurred in 260 patients (55.4%). There was no significant difference between the insulin resistance group (n = 260) and non-insulin resistance group (n = 210) as regards ovulation rate, number of follicles, serum E2 (pg/ml), serum progesterone (ng/ml), endometrial thickness (mm), or pregnancy rate. CONCLUSION: N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients.     

Ovulation induction

In the woman with anovulation and polycystic ovarian syndrome, there are many options for ovulation induction. Treatment should be individualized, but clomiphene citrate is an excellent first-line agent. In the woman resistant to clomiphene citrate, combination therapy often results in pregnancy. Some women with PCOS only respond to gonadotropin therapy. These women are at a higher risk for multiple pregnancy and ovarian hyperstimulation syndrome. In the woman with anovulation and hypothalamic amenorrhea, the options for ovulation induction are limited. The luteal phase must be supported. The hypothalamus is unable to support the corpus luteum or early pregnancy.     

Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate

OBJECTIVE: To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful. DESIGN: Prospective trial in infertility patients treated with CC. SETTING: Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences, University of Toronto. PATIENT(S): Twelve patients with anovulatory polycystic ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom had previously received CC with an inadequate outcome (no ovulation and/or endometrial thickness of < or =0.5 cm). INTERVENTION(S): The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3-7 after menses. MAIN OUTCOME MEASURE(S): Occurrence of ovulation, endometrial thickness, and pregnancy rates. RESULT(S): With CC treatment in patients with PCOS, ovulation occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women included in this study had endometrial thickness of < or =0.5 cm. In 10 ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature follicles, but all cycles had endometrial thickness of < or =0.5 cm on the day of hCG administration. With letrozole treatment in the same patients with PCOS, ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3 patients (25%). In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%). CONCLUSION(S): Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction.     

Endocrine methods of ovulation induction

The rationale of ovulation induction is to achieve the development of a single follicle and ultimately a singleton healthy baby. Problems faced by women with anovulatory polycystic ovary syndrome are the sensitivity of the ovary to stimulation and health issues such as obesity. This chapter will discuss medical management including strategies to lose weight, address hyperinsulinaemia with insulin-sensitizing agents, such as metformin, and outline methods of ovulation induction from the usual first-line therapy of clomiphene citrate and the subsequent use of gonadotrophin therapy in clomiphene-resistant patients. Appropriately directed surgical ovulation induction with laparoscopic ovarian diathermy appears to be as efficacious as gonadotrophin therapy but will not be discussed in the context of this chapter.     

Clomiphene citrate and ovulation induction

Clomiphene can be used to treat anovulation due to hypothalamus or pituitary gland dysfunction, and it normalizes the luteal phase in stimulated patients. It can be used to estimate ovarian follicle reserve, and may be predictive of ovulation in women aged >/=35 years or with failed IVF. Contraindications include risk of congenital anomalies, chronic liver disease and visual disorders. Clomiphene may impair fertility through its effects on cervical mucus and in causing various endometrial dysfunctions. However, if clomiphene is administered in 50 mg doses, side-effects are avoided and efficacy is similar to that of a 100 mg dose, although daily dosages of 200 mg/day over 5 days can induce ovulation in approximately 70% of treated patients. Gonadotrophin concentrations increase up to days 5-9 when follicles are selected, and clomiphene is effective in patients with polycystic ovary syndrome (PCOS). Fifty percent of normal patients conceive, a value perhaps biased by the antagonistic effects of clomiphene on cervical mucus in some women. Clomiphene is valuable for IVF, and is used by some clinics in combination with HMG or recombinant FSH. Resistance to clomiphene can develop, and human chorionic gonadotrophin may be needed to induce ovulation in clomiphene cycles. Corticosteroids and human menopausal gonadotrophin (HMG) can be combined with clomiphene for stimulation, its combination with HMG long having been a standard protocol in assisted reproduction. PCOS patients may become insulin resistant, a condition improved by the administration of metformin. Other adverse effects include multiple pregnancies, an increase in the rate of multiple births, ovarian hyperstimulation and unsubstantiated claims of ovarian cancer.     

A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome

OBJECTIVE: To compare the effectiveness of laparoscopic ovarian diathermy with gonadotropin ovulation induction for women with clomiphene citrate-resistant polycystic ovary syndrome. DESIGN: Randomized controlled trial. SETTING: A tertiary referral fertility clinic. PATIENT(S): Women with anovulatory infertility secondary to clomiphene-resistant polycystic ovary syndrome. Inclusion criteria were age of <39 years, body mass index of <35 kg/m(2), failure to ovulate with 150 mg of clomiphene citrate for 5 days in the early follicular phase, >12 months of infertility, and no other causes of infertility. INTERVENTION(S): Laparoscopic ovarian diathermy versus three cycles of urinary or recombinant gonadotropins. MAIN OUTCOME MEASURE(S): Cumulative pregnancy and miscarriage rates. RESULT(S): Cumulative pregnancy rates were 28% at 6 months for laparoscopic ovarian diathermy and 33% for three cycles of ovulation induction with gonadotropins. There were three miscarriages in each group. Women in the laparoscopic ovarian diathermy arm of the study had four additional spontaneous pregnancies 6 to 12 months after surgery. CONCLUSION(S): There was no statistically significant difference in pregnancy or miscarriage rates during the 6-month follow-up period or the three cycles. Laparoscopic ovarian diathermy is a safe and effective alternative to ovulation induction with gonadotropins.